gamma-crystallins are associated with cataract in both human and animal models. gS-crystallin is the major bg-crystallin in the adult human lens and has also been found to be induced in retinal pigment epithelium in models of macular degeneration. The gene for gS has been ablated in mouse, leading to disruption of normal fiber cell maturation. This is associated with abnormalities in key components of the architecture of the fiber cells, suggesting a functional role for crystallins in maintaining cell structure both in lens and elsewhere in the eye. Experiments are underway to measure directly the possible role of gS in assembly of key cellular structures. Examination of older knockout mice is also providing evidence for defects in other parts of the eye that may provide a model for aging. Collaborative studies using NMR structure analysis are shedding light on the processes of unfolding and amyloid formation in the mouse gS mutant Opj. This has wider significance for understanding how normally folded proteins can unfold and adopt other structures that can have serious consequences for cellular function. To explore the functional characteristics of g-crystallins, proteins from fish and birds representing the extremes of the family in composition and behavior have been expressed and are being compared by several biophysical techniques.